Blinatumomab plus ponatinib in adult patients with Philadelphia-positive ALL: Results from a phase II study

The historically used standard of care regimens for patients with Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) involve the combination of intensive chemotherapy and a BCR-ABL1 tyrosine kinase inhibitor (TKI), followed by allogeneic hematopoietic stem-cell transplantation (alloHSCT).

Whilst chemotherapy plus first- and second-generation BCR-ABL1 TKI’s have achieved overall survival rates of 40–50%, many patients (up to 75% of cases) with the ABL1 944C→T (Thr315Ile) mutation experience disease progression.¹

Ponatinib is a TKI that has demonstrated potent activity against the ABL1 944C→T (Thr315Ile) mutation. In frontline studies, ponatinib plus hyper-CVAD achieved high molecular response rates and showed encouraging clinical activity in adult patients with Ph+ ALL in combination with steroids, as previously reported on the ALL Hub.

Blinatumomab, a CD3-CD19 bispecific antibody, is an effective treatment for patients with relapsed/refractory (R/R) Ph+ ALL. Its recent combination with dasatinib, a second-generation BCR-ABL1 TKI with non-directed activity against Thr315Ile-mutated disease, proved safe and effective in patients with newly diagnosed Ph+ ALL.¹

Given the established efficacy of both ponatinib and blinatumomab-based regimens in Ph+ ALL and the prominent role of the Thr315Ile mutation in disease relapse, it has been suggested that a combination of these treatments may provide an effective chemotherapy-free option without the need for alloHSCT.

Below, we summarize a recent article by Jabbour et al. published in The Lancet Haematology examining the efficacy and safety of ponatinib combined with blinatumomab in adults with Ph+ ALL.¹

Study design

This is an ongoing, single-arm, single-center phase II trial (NCT03263572) carried out at the University of Texas MD Anderson Cancer Center, US. Included patients were ≥18 years of age and had

• newly diagnosed Ph+ ALL (including those who received one or two courses of chemotherapy, ± BCR–ABL1 TKI), R/R Ph+ ALL, as well as chronic myeloid leukemia in lymphoid blast phase (CML-LBP);
• Eastern Cooperative Oncology Group Performance Status of ≤2;
• total bilirubin 2 × the upper limit of normal or ≤2.4 mg/dLs;
• alanine aminotransferase, aspartate aminotransferase, serum lipase, and amylase concentrations ≤3 × the upper limit of normal; and
• central nervous system leukemia.

Treatment schedule

Up to five cycles of blinatumomab were administered as a continuous intravenous infusion.

• In cycle one, patients initially received blinatumomab 9 µg intravenously on Days 1 and 4, followed by 28 µg on Days 5–28; a standard dose of 28 µg was given in Cycles 2–5. Each cycle was followed by a 2-week treatment-free interval.
• In cycle one, patients initially received ponatinib 30 mg orally daily, which was reduced to 15 mg daily once a complete molecular response was achieved. After completion of blinatumomab, ponatinib was given as maintenance therapy for up to 5 years. All patients were given 12 doses of intrathecal chemotherapy for central nervous system prophylaxis.

Endpoints

The primary endpoints were:

1. Complete molecular response in patients with newly diagnosed Ph+ ALL, defined as lack of a detectable BCR-ABL1 transcript by polymerase chain reaction at a sensitivity of 0.01%.
2. Overall response rate, defined as complete response (CR) + complete response with incomplete hematological recovery (CRi), in patients with R/R Ph+ ALL or CML-LBP.

The secondary endpoints within all cohorts included safety, event-free survival (EFS), and overall survival (OS).

Results

Baseline characteristics

In total, 60 patients were treated with combined blinatumomab and ponatinib, 40 of whom had newly diagnosed Ph+ ALL, 14 had R/R Ph+ ALL, and six had CML-LBP. Baseline characteristics for each cohort are summarized in Table 1.

Table 1. Selected baseline characteristics of patients with newly diagnosed and R/R Ph+ ALL*

Efficacy

The median number cycles received was five for the newly diagnosed cohort and three for both the R/R Ph+ ALL and CML-LBP cohorts. Responses in the newly diagnosed, R/R Ph+ ALL, and CML-LBP cohorts are summarized in Table 2.

In the newly diagnosed cohort, 28 patients were included in the hematologic response analysis and 12 were excluded due to CR at enrolment.

In the newly diagnosed cohort (n = 40),

• one patient died early due to prior chemotherapy given before trial enrolment;
• one patient died due to hypovolaemic shock after one complete treatment cycle;
• alloHSCT was given to one patient during the first response, who had BCR-ABL1 levels of 0.01–0.05%, with the remaining 37 not receiving alloHSCT;
• six patients discontinued therapy (3 due to toxicities, 1 due to loss of insurance, 1 due to minimal residual disease positivity, and 1 due to early death); and
• 1-year EFS and OS rates were 95% at a median follow-up of 15 months, with no relapses or disease-related deaths.

In the R/R cohort (n = 14), 13 patients were evaluable for hematological responses;

• six patients underwent alloHSCT following treatment response (one relapsed thereafter and five experienced ongoing remission);
• of the four patients who did not receive alloHSCT, one experienced disease progression, one died, and two remained in ongoing remission; and
• 1-year EFS and OS rates were 57% and 79%, respectively, at a median follow-up of 22 months.

In the CML-LBP cohort (n = 6),

• three patients experienced disease progression while two remained in ongoing remission; and
• the estimated 1-year EFS and OS rates were 50% and 100%, respectively, after a median follow-up of 25 months.

Table 2. Hematologic, molecular response rates, and survival analysis for all cohorts*

Safety

The serious adverse events (AEs) most observed in ≥5% of all treated patients (n = 60) were infection and febrile neutropenia, increased lipase and amylase concentration, increased alanine or aspartate aminotransferase concentration, hypertension, pain, and hyperglycemia (Table 3). There were no Grade 4–5 treatment-related AEs reported overall.

Dose reductions due to treatment-related AEs were seen in a total of five patients (ponatinib reductions in the newly diagnosed cohort [3 patients] and blinatumomab-related reductions in the R/R cohort [2 patients]).

Discontinuation of blinatumomab and ponatinib due to treatment-related AEs occurred in one and three patients, respectively.

Table 3. Serious AEs reported in ≥5% of patients*

Conclusion

In this phase II study, ponatinib in combination with blinatumomab proved effective and safe as a chemotherapy-free approach for adult patients with newly diagnosed and R/R Ph+ ALL. The combination demonstrated deep molecular and durable hematologic responses, reducing the need for alloHSCT and outlining its potential as a transplant-sparing regimen in the frontline setting. Whilst a combination of ponatinib and blinatumomab presents a promising regimen for Ph+ ALL, longer follow-up analyses are needed to further establish its clinical efficacy.